9-Phenyl 5,6-dimethyl-nona-2,4,6,8 tetraenal or tetraenol derivatives

ABSTRACT

Novel 9-phenyl 5,6-dimethyl-nona-2,4,6,8-tetraenoic acid, tetraenal or tetraenol derivatives useful as anti-tumor agents.

This is a division of application Ser. No. 903,438, filed May 8, 1978,now abandoned, which in turn is a division application of Ser. No.714,170, filed Aug. 13, 1976, now U.S. Pat. No. 4,105,681, which in turnis a continuation-in-part application of Ser. No. 601,148, filed Aug. 1,1975, now abandoned, which in turn is a continuation-in-part applicationof Ser. No. 454,007, filed Mar. 22, 1974, now abandoned.

SUMMARY OF THE INVENTION

In accordance with this invention, it has been found that compounds ofthe formula: ##STR1## wherein R₁ and R₂ are lower alkyl; R₃ is hydrogen,lower alkyl, lower alkoxy, lower alkenyloxy, nitro, halo, amino, loweralkyl-amino, lower alkanoylamino, or N-heterocyclyl; R₄ is hydrogen,lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, nitro, loweralkanoyloxy, amino, lower alkylamino or N-heterocyclyl; R₅ is hydrogen,lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, nitro, halo,amino, lower alkanoylamino, lower alkyl amino, or N-heterocyclyl; withthe proviso that at least one of R₃, R₄, and R₅ is other than hydrogen;with the further proviso that when R₃ or R₅ is halogen, R₄ is other thanalkoxy; R₆ is formyl, hydroxymethylene, alkoxymethylene,alkanoyloxymethylene, carboxyl, alkoxycarbonyl, alkenloxycarbonyl,alkynyloxycarbonyl, carbamoyl, mono (lower alkyl)-carbamoyl, di (loweralkyl)-carbamoyl, or N-heterocyclylcarbonyl; or pharmaceuticallyacceptable salts thereof are useful as anti-tumor agents.

The compounds of formula I are prepared by the reaction of a compound ofthe formula: ##STR2## with a compound of the formula: ##STR3## whereinR₁, R₂, R₃, R₄ and R₅ are as above; m and n are integers of from 0 to 1with the sum of m and n being equal to 1; one of A or B being oxo andthe other being: ##STR4## one of A and B is ##STR5## R₂₀ and the otherbeing halogen, alkylsulfonyloxy or arylsulfonyloxy; X is aryl; Z isalkoxy; R₂₀ is aryl, aralkenyl, aryl substituted with an electrondonating or electron withdrawing group or aralkenyl where the arylmoiety is substituted with an electron withdrawing or electron donatinggroup; R₇, when ##STR6## is formyl, carboxy, alkoxycarbonyl,alkenyloxycarbonyl, alkynyloxycarbonyl, di (lower alkyl) carbamoyl orN-heterocyclylcarbonyl; R₇, when B is oxo, is carboxy, alkoxymethylene,alkanoyloxymethylene, alkoxycarbonyl, alkenyloxycarbonyl,alkynyloxycarbonyl or N-heterocyclylcarbonyl, R₇, when B is halogen,alkylsulfonyloxy or arylsulfonyloxy, is formyl, carboxy,alkoxymethylene, alkanoyloxymethylene, alkoxycarbonyl,alkenyloxycarbonyl; alkynyloxycarbonyl, di (lower alkyl)-aminocarbamoyl, or N-heterocyclylcarbonyl, and Y is an anion of an organic orinorganic acid.

In the case where one of A or B form the sulfone group which containsthis sulfone group: ##STR7## This sulfone group in the reaction productcan be cleaved to a double bond to form the compound of formula I. Inthe reaction products of the compound of formula II and III, where R₇ isa carboxyl group, this carboxyl group can be esterified or amidated. Onthe other hand, where R₇ is a carboxyl group or an ester group, thisreaction product can be reduced to form R₇ as a hydroxy group. Where thereaction product contains R₇ as a hydroxy group, this group can beesterified or etherified. The resulting alcohol ester can, if derived,be saponified. On the other hand, where R₇ in the reaction product is afree hydroxy group or an ester group, this reaction product can beoxidized and form the corresponding compound where R₇ is carboxyl, i.e.,--COOH.

DETAILED DESCRIPTION

The term "halogen", as utilized in the instant specification, denotesall four halogens, i.e., chlorine, bromide, iodine and fluorine, withchlorine and bromine being preferred. The term "lower alkyl" denotesboth straight chain and branched chain lower alkyl groups containingfrom 1 to 6 carbon atoms such as methyl, ethyl, isopropyl and2-methylpropyl. The term "lower alkoxy" as used throughout thisspecification denotes lower alkoxy groups containing from 1 to 7 carbonatoms such as methoxy, propoxy, isopropoxy, ethoxy, etc. The term "loweralkanoyl" denotes lower alkanoyl groups containing from 2 to 6 carbonatoms such as acetyl, propionyl or pivalonyl.

The terms "lower alkenyl" and "lower alkynyl" includes both straightchain and branched chain hydrocarbon groups containing from 2 to 6carbon atoms such as vinyl, allyl, butenyl, pentenyl, ethynyl,propargyl, butynyl, etc.

The term N-heterocyclyl designates N-heterocyclyl radicals containingpreferably 5 or 6 membered rings which contain a nitrogen atom in thering and which can, if desired, contain a further hetero atom selectedfrom the group consisting of oxygen, nitrogen or sulfur. Among thepreferred N-heterocyclyl radicals are included pyrrolidino, pyridino,piperidino, morpholino or thiomorpholino.

The lower alkanoylamino groups contain residues which are derived fromlower alkanecarboxylic acids containing from 2 to 6 carbon atoms (e.g.acetic acid, propionic acid or pivalic acid).

The alkoxymethylene and alkoxycarbonyl groups preferably contain alkoxymoieties having from 1 to 6 carbon atoms. These can be straight-chain orbranched-chain such as, for example, the methoxy, ethoxy and isopropoxygroups. However, the alkoxy moiety can also be a higher alkoxy groupcontaining from 7 to 20 carbon atoms, especially the cetyloxy group. Thealkoxy moiety can be substituted by functional groups; for example, bynitrogen-containing groups such as, for example, by an amino ormorpholino group, which may be alkyl-substituted, or by a piperidyl orpyridyl group.

The alkenyloxycarbonyl and alkynyloxycarbonyl groups preferably containalkenoxy and alkynoxy moieties having from 2 to 6 carbon atoms such as,for example, the allyloxy or propargyloxy group.

The term "alkanoyloxy" designates derivatives of alkanecarboxylic acidscontaining from 2 to 20 carbon atoms. Among the preferred loweralkanoyloxy groups are included lower alkanoyloxy groups containing from2 to 6 carbon atoms such as acetyloxy, propionyloxy and pivalyloxy.However, the alkanoyloxy group can be derived from higher alkanecarboxylic acids, i.e., acids containing from 6 to 20 carbon atoms suchas palmitic acid or stearic acid as well as lower alkanoyloxy groups.The term "alkanoyloxymethylene" denotes alkanoyloxymethylene groupswherein alkanoyloxy is defined as above. Among the preferredalkanoyloxymethylene groups are included acetyloxymethylene andpropionyloxymethylene.

The terms "mono" and "di (lower alkyl) carbamoyl" denote mono and di(lower alkyl) carbamoyl radicals wherein lower alkyl is defined asabove. Among the preferred mono or di (lower alkyl) carbamoyl groups areincluded such groups as N-methyl-carbamoyl, N,N-dimethylcarbamoyl,N-isopropylcarbamoyl, and N-tertiarybutylcarbamoyl. The"N-heterocyclylcarbonyl" radicals are those which preferably contain a 5or 6 membered heterocyclic ring, which in addition to the nitrogen atommay contain a further hetero atom selected from the group consisting ofnitrogen, oxygen or sulfur. Examples of such N-heterocyclic groups whichcan be utilized in accordance with this invention are included pyridino,piperidino, morpholino, thiomorpholino and pyrrolidino.

In the compound of formula I, the preferred di (lower alkyl) aminogroups denoted are those where the lower alkyl substituent contains from1 to 4 carbon atoms. Among the preferred lower alkyl amino groups areincluded ethyl amino, dimethyl amino, diethyl amino and diisopropylamino. The term lower alkyl amino includes both mono and di-lower alkylamino groups.

Among the preferred compounds of formula I are the following:

9-(2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic-acid;

9-(2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid;

9-(2,4,6-triisopropyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic-acid;

9(2,3,4,6-tetramethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid;

9-(4-methoxy-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic-acid;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid;

9-(3-methoxy-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic-acidethyl ester;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2-trans, 4-cis,6-trans, 8-trans-tetraen-1-oic acid ethyl ester;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid isopropyl ester;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid diethylaminoethyl ester;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid amide;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl amide;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid allyl ester;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid propargyl ester;

9-(3,6-dimethoxy-2,4,5-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid;

9-(4-methoxy-3-allyl-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid;

9-(4-methoxy-3-nitro-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester;

9-(3-dimethylamino-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester;

9-(4-isopropoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid;

9-(4-allyloxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid;

9-(5-chloro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid; and

9-(3-nitro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid.

The toxicity of the compounds of formula I is slight. For example, aswill be evident from the following Table, the acute toxicity [LD₅₀ ] of9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid [A] and of9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester [B] in mice after intraperitoneal administration inrape-oil lies at 700 or 1000 mg/kg.

                  Table                                                           ______________________________________                                        Acute Toxicity                                                                ______________________________________                                        Substance A                                                                              LD.sub.10 mg/kg                                                                          LD.sub.50 mg/kg                                                                          LD.sub.90 mg/kg                              ______________________________________                                        After 1 day                                                                              >4000      >4000      >4000                                        After 10 days                                                                            580        700        890                                          After 20 days                                                                            580        700        890                                          ______________________________________                                        Substance B                                                                              LD.sub.10 mg/kg                                                                          LD.sub.50 mg/kg                                                                          LD.sub.90 mg/kg                              ______________________________________                                        After 1 day                                                                              >4000      >4000      >4000                                        After 10 days                                                                            1400       1900       2600                                         After 20 days                                                                            710        1000       1400                                         ______________________________________                                    

The compounds of formula I are effective for utilizing tumors such aspapillomas. In the papilloma test, tumors induced withdimethylbenzanthracene and croton oil regress. The diameters of thepapillomae decline within 2 weeks on intraperitoneal administration. Inthe case of substance A, the decline is by 38% at 50/mg/kg/week and by69% at 100 mg/kg/week and in the case of substance B the decline is by45% at 25 mg/kg/week and by 63% at 50 mg/kg/week.

The compounds of formula I are also useful as medicaments for thetopical and systemic therapy of acne, psoriasis and other relateddermatological disorders which are characterized by an increased orpathologically altered cornification, as well as inflammatory andallergic dermatological conditions. They can also be used to treatdisorders which are characterized by inflammatory or degenerativealterations of the mucous membranes.

The polyene compounds of formula I can accordingly be used asmedicaments; for example, in the form of pharmaceutical preparationswhich contain them in association with a compatible pharmaceuticalcarrier. The pharmaceutical preparations serving for systemicapplication can, for example, be produced by adding a polyene compoundof formula I as the active ingredient to non-toxic, inert, solid orliquid carriers which are usual in such preparations. The pharmaceuticalpreparations can be administered enterally or parenterally. Suitablepharmaceutical preparations for enteral administration are, for example,tablets, capsules, dragees, syrups, suspensions, solutions andsuppositories. Pharmaceutical preparations in the form of infusion orinjection solutions are suitable for parenteral administration.

The dosages in which the polyene compounds of formula I can beadministered can vary according to the mode of administration and routeof administration as well as according to the requirements of thepatient.

The polyene compounds of formula I can be administered in amounts offrom 5 mg. to 200 mg. daily in one or more dosages. Capsules with acontent of a ca 10 mg. to ca 100 mg. of a polyene compound are apreferred form of presentation.

The pharmaceutical preparations can contain inert or otherpharmacodynamically active additives. Tablets or granules, for example,can contain a series of binding agents, fillers, carrier materials ordiluents. Liquid preparations can, for example, take the form of asterile water-miscible solution. Besides the polyene compounds offormula I, capsules can additionally contain a filling material orthickening agent. Furthermore, flavor-improving additives as well as thesubstances usually used as preserving, stabilizing, moisture-retainingor emulsifying agents, salts for varying the osmotic pressure, buffersand other additives can be present.

The carrier materials and diluents mentioned hereinbefore can be organicor inorganic substances; for example, water, gelatin, lactose, starches,magnesium stearate, talcum, gum arabic, polyalkyleneglycols and thelike. It is of course a prerequisite that all adjuvants used in theproduction of the pharmaceutical preparations are non-toxic.

For topical administration, the polyene compounds of formula I areexpediently made up in the form of ointments, tinctures, creams,solutions, lotions, sprays, suspension and the like. Ointments andcreams, as well as solutions, are preferred. These pharmaceuticalpreparations intended for topical administration can be produced bymixing the polyene compounds as the active ingredient with non-toxic,inert solid or liquid carriers suitable for topical administration whichare usual per se in such preparations.

Expedient for topical administration are ca 0.01% to ca 0.3% (preferably0.02% to 0.1%) solutions as well as ca 0.05% to ca 5% (preferably ca0.1% to ca 2.0%) ointments or creams.

An antioxidant (e.g. tocopherol, N-methyl-γ-tocopheramine, butylatedhydroxyanisole or butylated hydroxytoluene can optionally be added tothe pharmaceutical preparations.

The aryl groups denoted by X in the triarylphosphonium groups of theformula --P[X]₃ ⁺ Y⁻ in the compounds of formula II or III include allgenerally known aryl groups, but especially mononuclear aryl groups suchas phenyl, lower alkyl-substituted phenyl or lower alkoxy-substitutedphenyl (e.g. tolyl, xylyl, mesityl and p-methoxyphenyl). Of theinorganic acid anions denoted by Y, the chlorine, bromide, iodide andhydrosulphate ions are preferred and, of the organic acid anions, thetosyloxy ion is preferred.

The alkoxy groups denoted by Z in the dialkoxyphosphinyl groups of theformula ##STR8## are preferably lower alkoxy groups containing from 1 to6 carbon atoms, especially methoxy and ethoxy.

The preferred electron withdrawing groups are those which are weaklyelectron withdrawing. Examples of aryl and aralkenyl groups, which maybe substituted by one or more electron donating to weaklyelectron-withdrawing substituents, denoted by R₂₀ in the sulfone groupof the formula: ##STR9## are phenyl and styryl which may be substitutedin the o-, m- or p-position by methoxy, phenoxy, acetoxy, dimethylamino,phenylmethylamino, acetylamino, thiomethyl, thiophenyl, thioacetyl,chloro, bromo or cyano or in the m-position by nitro.

The starting materials of formulae II and III are, in part, novelcompounds.

Compound of formula II where m is O and A is a triarylphosphonium grouphave the following formula: ##STR10## wherein R₁, R₂, R₃, R₄, R₅, X andY are as above. Compounds of the formula II where m is O and A is adialkoxy phosphnyl group have the following formula: ##STR11## whereinR₁, R₂, R₃, R₄, R₅ and Z are as above: The compounds of formula II-a andII-c can be prepared, for example, by treating a corresponding (R₁ -R₅)substituted-benzene with formaldehyde in the presence of a hydrohalicacid (e.g. concentrated hydrochloric acid), if desired in a solvent(especially glacial acetic acid) to prepare a compound of formula IIwhere m is O and A is a halogen, i.e., the compound of formula II-i. Thehalide of formula II-i is reacted in a converted manner with a triarylphosphine in a solvent, preferably with triphenyl phosphine in tolueneor benzene, or with a trialkyl phosphite, especially with triethylphosphite.

An alkoxy group present in the aforementioned (R₁ -R₅)-benzene can beintroduced, for example, by alkylation of a hydroxy group present. Forexample, the corresponding phenol can be reacted, preferably in asolvent (e.g. an alkanol) and in the presence of a base (e.g. potassiumcarbonate), with an alkyl halide (e.g. methyl iodide) or dimethylsulphate.

Compounds of formula II where m is 1 and A is a triaryl phosphoniumgroup have the formula: ##STR12## wherein R₁, R₂, R₃, R₄, R₅, X and Yare as above. Compounds of formula II where m is 1 and A isdialkoxyphosphinyl have the formula: ##STR13## wherein R₁, R₂, R₃, R₄,R₅ and Z is as above; The compounds of formula II-b and II-d can beprepared by first formylating the corresponding (R₁ -R₅)-benzene. Thiscan be carried out, for example, by formylating the (R₁-R₅)substituted-benzene in the presence of a Lewis acid. As theformylating agent there can be used, in particular, an orthoformic acidester, formyl chloride and dimethylformamide. Especially suitable Lewisacids are the halides of zinc, aluminium, titanium, tin and iron such aszinc chloride, aluminium trichloride, titanium tetrachloride, tintetrachloride and iron trichloride as well as the halides of inorganicand organic acids such as, for example, phosphorus oxychloride andmethane sulfochloride.

If the formylating agent is present in excess, the formylation may becarried out without the addition of a further solvent. In general,however, it is recommended to carry out the formylation in an inertsolvent (e.g. nitrobenzene or in a chlorinated hydrocarbon such asmethylene chloride). The formylation can be carried out at a temperaturebetween 0° C. and the boiling point of the mixture.

A resulting (R₁ -R₅)-benzaldehyde can subsequently be chain-lengthenedin a conventional manner by condensation with acetone in the cold (i.e.at a temperature of about 0°-30° C.) in the presence of alkali (e.g.dilute aqueous sodium hydroxide to give a (R₁ -R₅)-phenyl-but-3-en-2-onewhich can be converted into the corresponding (R₁-R₅)-phenyl-3-methyl-3-hydroxy-penta-4-en-1-yne in a manner known per seby means of an organometallic reaction (e.g. by means of a Grignardreaction by the addition of acetylene). The resulting tertiary ethyleniccarbinol can subsequently be partially hydrogenated in a conventionalmanner using a partially deactivated noble metal catalyst (lindlarcatalyst). The resulting tertiary ethylenic carbinol can subsequently beconverted, under allyl rearrangement, into the desired phosphonium saltof formula II-b where m stands for 1 by treatment with a triarylphosphine, especially with triphenyl phosphine, in the presence of ahydrohalide such as hydrogen chloride or hydrogen bromide in a solvent(e.g. in benzene). The tertiary ethylenic carbinol can, moreover, behalogenated to give the compound of formula II where m is 1 and A is ahalide, i.e. the compound of formula II-k. This halide of formula II-kcan be reacted with a trialkyl phosphite (e.g. triethyl phosphite) togive a corresponding phosphonate of formula II-d.

Compounds of formula II where m is 0 and A is a sulfone group have theformula: ##STR14## wherein R₁, R₂, R₃, R₄, R₅ and R₂₀ are as above.Compounds of formula II-e can be prepared, for example, by dissolving a(R₁ -R₅)-phenol or a corresponding halobenzene in a polar solvent suchas an alcohol (e.g. methanol, ethanol or isopropanol) or intetrahydrofuran or dimethylformamide or in glacial acetic acid andtreating the solution at room temperature with a sulfinic acid of theformula: ##STR15## wherein R₂₀ is as above, or with an alkali saltthereof. The sulfone can be isolated, for example, by making thereaction mixture neutral by adding an aqueous sodium hydrogen carbonatesolution and extracting the sulfone with an organic solvent (e.g. ethylacetate or ether).

Compounds of formula II where m is 1 and A is a sulfone group having theformula: ##STR16## wherein R₁, R₂, R₃, R₄, R₅ and R₂₀ are as above;Compounds of formula II-f can be prepared in an analogous manner byreacting a (R₁ -R₅)-phenyl-3-methyl-penta-2,4-dien-1-ol or a halidethereof with a sulfinic acid as set forth hereinabove or with an alkalisalt thereof.

Compounds of formula II where m is zero and A is oxo, i.e., the compoundof formula II-g can be prepared, for example, by formylating in thepreviously described manner a (R₁ -R₅)-benzene. In this manner, a (R₁-R₅)-benzaldehyde is directly obtained from the (R₁ -R₅) benzene.

Compounds of formula II where m is 1 and A is oxo, i.e., the compound offormula II-h can be prepared, for example, by submitting a (R₁-R₅)-phenyl-but-3-en-2-one, described hereinbefore in connection withthe preparation of compounds of formula II-b, to a Wittig reaction withethoxycarbonyl-methylene-triphenylphosphorane or withdiethyl-phosphonoacetic acid ethyl ester. The resulting (R₁-R₅)-phenyl-3-methyl-penta-2,4-dien-1-oic acid ethyl ester issubsequently reduced in the cold with a mixed metal hydride, especiallylithium aluminium hydride, in an organic solvent (e.g. diethyl ether ortetrahydrofuran) to give a (R₁ -R₅)-phenyl-3-methyl-penta-2,4-dien-1-ol.This alcohol is then oxidized by treatment with an oxidizing agent, forexample, with manganese dioxide in an organic solvent such as acetone ormethylene chloride at a temperature between 0° C. and the boiling pointof the mixture to give the desired (R₁-R₅)-phenyl-3-methyl-penta-2,4-dien-1-al of formula II-h.

The compounds of formula III are also, in part, novel.

Compounds of formula III where n is zero and B is a triarylphosphoniumgroup [III-a] or a dialkoxyphosphinyl group [III-c] can be readilyprepared by reacting an optionally esterified 3-halomethyl-crotonic acidor an etherified 3-halomethyl-crotyl alcohol with a triaryl phosphine ina solvent, preferably with triphenyl phosphine in toluene or benzene, orwith a trialkyl phosphite, especially with triethyl phosphite.

Compounds of formula III where n is 1 and B is a triarylphosphoniumgroup [III-b] or a dialkoxyphosphinyl group [III-d] can be prepared, forexample, by reducing the formyl group of an aldehyde of formula III-h inwhich n stands for 1 to the hydroxymethyl group using a metal hydridesuch as sodium borohydride in an alkanol (e.g. ethanol or isopropanol).The resulting alcohol can be halogenated using a conventionalhalogenating agent (e.g. phosphorus oxychloride) and the resulting8-halo-3,7-dimethyl-octa-2,4,6-triene-1-carboxylic acid (a halide offormula III in which n stands for 1 and B is halogen) or a derivativethereof can be reacted either with a triaryl phosphine in a solvent,preferably with triphenyl phosphine in toluene or benzene, to give adesired phosphonium salt of formula III-b or with a trialkyl phosphite,especially with triethyl phosphite, to give a desired phosphonate offormula III-d.

Compounds of formula III-e where n is zero and B is a sulfone group canbe prepared, for example, by reacting 4-hydroxy-3-methyl-but-2-en-1-alor the corresponding acetate or bromide in a polar solvent (e.g.isopropanol or n-butanol) in the manner previously described with one ofthe sulfinic acids defined hereinbefore or with an alkali metal saltthereof.

Compounds of formula III-f where n is 1 and B is a sulfone group can beprepared in a manner analogous to that described earlier by the reactionof, for example, 8-hydroxy-3,7-dimethyl-octa-2,4,6-trien-1-oic acid orthe corresponding acetate or bromide of this alcohol with a sulfinicacid as hereinbefore defined or with an alkali metal salt thereof.

Compounds of formula III-g where n is zero and B is an oxo group can beprepared, for example, by oxidatively cleaving an optionally esterifiedtartaric acid; for example, using lead tetraacetate at room temperaturein an organic solvent such as benzene. The resulting glyoxalic acidderivative is subsequently condensed in a manner known per se,conveniently in the presence of an amine, with propionaldehyde at anelevated temperature (e.g. at a temperature between 60° C. and 110° C.)with water cleavage to give the desired 3-formyl-crotonic acidderivative.

Compounds of formula III-h where n is 1 and B is an oxo group can beprepared, for example, by reacting 4,4,-dimethoxy-3-methyl-but-1-en-3-olwith phosgene in the cold, preferably at -10° C. to -20° C., in thepresence of a tertiary amine such as pyridine and condensing theresulting 2-formyl-4-chloro-but-2-ene under conditions of a Wittigreaction with an optionally esterified 3-formyl-crotonic acid or to anoptionally esterified or etherified 3-formyl-crotyl alcohol to give thedesired aldehyde of formula III-b.

According to the process provided by the present invention, thefollowing reactions are effected:

phosphonium salts of formula II-a or II-b are reacted with aldehydes offormula III-h or III-g,

phosphonium salts of formula III-a or III-b are reacted with aldehydesof formula II-h or II-g, or

phosphonates of formula II-c or II-d are reacted with aldehydes offormula III-h or III-g, or

phosphonates of formula III-c or III-d are reacted with aldehydes offormula II-h or II-g, or

sulfones of formula II-e or II-f are reacted with halides of formulaIII-k or III-i, or

sulfones of formula III-e or III-f are reacted with halides of formulaII-k or II-i.

According to the Wittig procedure, the reaction components are reactedwith one another in the presence of an acid binding agent, for example,in the presence of an alkali metal alcoholate such as sodium methylateor in the presence of an optionally alkyl-substituted alkylene oxide,especially in the presence of ethylene oxide or 1,2-butylene oxide, ifdesired in a solvent (e.g. in a chlorinated hydrocarbon such asmethylene chloride or in dimethylformamide) at a temperature betweenroom temperature and the boiling point of the reaction mixture.

According to the Horner procedure, the reaction components are reactedwith one another with the aid of a base and preferably in the presenceof an inert organic solvent; for example, with the aid of sodium hydridein benzene, toluene, dimethylformamide, tetrahydrofuran, dioxan or1,2-dimethoxyethane or with the aid of an alkali metal alcoholate in analkanol (e.g. sodium methylate in methanol) at a temperature between 0°C. and the boiling point of the reaction mixture.

According to the Julia procedure, the reaction components are reactedwith one another with the aid of a condensation agent, conveniently inthe presence of a polar solvent. Suitable solvents are, for example,dimethylformamide, dimethyl sulphoxide, dimethylacetamide,tetrahydrofuran and hexamethylphosphoric acid triamide as well asalkanols such as methanol, isopropanol or tertbutanol. Examples ofstrong bases which are preferably used as the condensation agent arealkali metal carbonates (especially sodium carbonate), alkaline earthmetal carbonates, alkali metal hydroxides (e.g. sodium hydroxide orpotassium hydroxide), alkali metal alcoholates (e.g. sodium methylateand, especially, potassium tertbutylate), alkaline earth metalalcoholates, alkali metal hydrites (e.g. sodium hydride),alkyl-magnesium halides (e.g. methyl-magnesium bromide) and alkali metalamides (e.g. sodium amide). The reaction is expediently carried out at alow temperature, especially at a temperature below the freezing point(e.g. between -50° C. and -80° C.) It has been shown to be convenient incertain cases to carry out the reactions described hereinbefore in situ;i.e. without isolating the phosphonium salt, phosphonate or sulfone fromthe medium in which it is prepared.

A carboxylic acid of formula I can be converted in a manner known per se(e.g. by treatment with thionyl chloride, preferably in pyridine) intoan acid chloride which can be converted by treatment with ammonia intoan amide and by reaction with an alkanol into an ester.

A carboxylic acid ester of formula I can be hydrolysed in a manner knownper se (e.g. by treatment with an alkali, especially aqueous-alcoholicsodium hydroxide or potassium hydroxide) at a temperature between roomtemperature and the boiling point of the mixture and then amidatedeither via an acid halide or as described hereinafter.

A carboxylic acid ester of formula I can be converted directly into acorresponding amide, for example, by treatment with lithium amide. Thelithium amide is advantageously treated with the ester at roomtemperature.

A carboxylic acid or a carboxylic acid ester of formula I can be reducedin a manner known per se to give a corresponding alcohol of formula I.The reduction is advantageously carried out using a metal hydride oralkyl metal hydride in an inert solvent. The preferred hydrides are themixed metal hydrides such as lithium aluminium hydride orbis[methoxy-ethylenoxy]-sodium aluminium hydride. Suitable solvents are,inter alia, ether, tetrahydrofuran or dioxan when lithium aluminiumhydride is used and ether, hexane, benzene or toluene when diisobutylaluminium hydride or bis[methoxy-ethylenoxy]-sodium aluminium hydride isused.

An alcohol of formula I can be etherified with an alkyl halide (e.g.ethyl iodide), for example, in the presence of a base, preferably sodiumhydride, in an organic solvent such as dioxan, tetrahydrofuran,1,2-dimethoxyethane, dimethylformamide or in the presence of an alkalimetal alcoholate in an alkanol at a temperature between 0° C. and roomtemperature.

An alcohol of formula I can also be esterified by treatment with analkanoyl halide or anhydride, expediently in the presence of a base(e.g. pyridine or triethylamine) at a temperature between roomtemperature and the boiling point of the mixture.

An alcohol ester can be saponified in a manner known per se; forexample, in the manner previously described in connection with thehydrolysis of a carboxylic acid ester.

An alcohol of formula I or an ester thereof can be oxidized in a mannerknown per se to give a corresponding acid of formula I. The oxidation isadvantageously carried out with silver (I) oxide and alkali in water orin an organic water-miscrible solvent at a temperature between roomtemperature and the boiling point of the mixture.

An amine of formula I forms addition salts with inorganic and organicacids. Examples of such salts are those formed with hydrohalic acids(especially with hydrochloric or hydrobromic acid), with other mineralacids (e.g. with sulphuric acid) and with organic acids (e.g. withbenzoic acid, acetic acid, citric acid or lactic acid).

A carboxylic acid of formula I forms salts with bases, especially withalkali metal hydroxides and especially with sodium hydroxide orpotassium hydroxide.

The compounds of formula I can occur as cis/trans mixtures which, ifdesired, can be separated into the cis and trans components orisomerised to the all-trans compounds in a manner known per se.

The following examples are illustrative but not limitative of thisinvention. In the examples, the ether utilized was diethyl ether. In theexamples concentrated hydrochloric acid denotes an aqueous solutioncontaining about 37% by weight hydrochloric acid. The term 35%formaldehyde which appears in the Examples indicates an aqueous solutioncontaining 35% formaldehyde. The term "low boiling petroleum ether" asused in the examples designates petroleum ether boiling at °C.

The sodium hydride (50-60%) utilized in the examples refers to a mineraloil suspension containing 30 to 60% by weight sodium hydride.

EXAMPLE 1

228 g of5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1-triphenylphosphoniumbromide are introduced under nitrogen gassing into 910 ml ofdimethylformamide and treated with cooling at 5°-10° C. within 20minutes with 17.5 g of a suspension of sodium hydride (about 50% byweight) in mineral oil. The mixture is stirred for 1 hour at about 10°C., then treated at 5°-8° C. dropwise with 61.8 g of 3-formylcrotonicacid butyl ester, heated for 2 hours at 65° C., subsequently introducedinto 8 l of ice-water and, after the addition of 300 g of sodiumchloride, thoroughly extracted with a total of 18 l of hexane. Theextract is washed 5 times with 1 l of methanol/water (6:4 parts byvolume) each time and 2 times with 1.5 l of water each time, dried oversodium sulphate and evaporated under reduced pressure to leave9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid butyl ester, m.p. 80°-81° C. as the residue.

EXAMPLE 2

125.8 g of9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid butyl ester are introduced into 2000 ml of abs. ethanol and treatedwith a solution of 125.8 g of potassium hydroxide in 195 ml of water.The mixture is heated to boiling under nitrogen gassing for 30 minutes,then cooled, introduced into 10 l of ice-water and, after the additionof about 240 ml of conc. hydrochloric acid [pH 2-4], thoroughlyextracted with a total of 9 l of methylene chloride. The extract iswashed with about 6 l of water to neutrality, dried over calciumchloride and evaporated under reduced pressure. The residue is taken upin 700 ml of hexane. The precipitated9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid melts at 228°-230° C.

EXAMPLE 3

500 g of 2,3,5-trimethylphenol are introduced into 1840 ml of ethanoland 184 ml of water and treated, with gentle stirring, with 240 g ofpotassium hydroxide. To the resulting clear solution, there are addeddropwise at 0°-5° C. within 30-45 minutes 626 g of methyl iodide. Thereaction mixture is stirred for 2 hours at room temperature,subsequently stirred under reflux conditions for 12 hours at 60° C.,then treated with 5 l of water and thoroughly extracted with a total of6 l of diethyl ether. The extract is washed first with 3 l of 3 aqueoussodium hydroxide, then washed 2 times with 1 l of water each time, driedover sodium sulphate and evaporated under reduced pressure. Theremaining 2,3,5-trimethylanisole, after rectification, boils at 88°-90°C./10 mm Hg.

184 g of phosphorus oxychloride are added dropwise to 87.1 g ofdimethylformamide with stirring at 10°-20° C. within 20-30 minutes. Thetemperature should rise to 25° C. towards the end of the addition. Intothe obtained mixture, there are introduced 150 g of2,3,5-trimethylanisole within 20 minutes with cooling at 10°-20° C. Thereaction mixture is slowly heated up to max. 115° C., stirred for 6hours at 100° C. for the completion of the reaction, poured, aftercooling, into 2 kg of ice/water 1:1 parts by volume and, after theaddition of 1500 ml of benzene, treated with 500 g of sodium acetate.The water phase which forms is separated after stirring for 1 hour andagain extracted with 1000 ml of benzene. The combined benzene extractsare washed successively with 480 ml of 1.5 aqueous hydrochloric acid and500 ml of water, dried over sodium sulphate and filtered over 20 g ofdecoloring carbon. The filtrate is evaporated under reduced pressure.The remaining 2,3,6-trimethyl-p-anisaldehyde melts, afterrecrystallisation from hexane at 65°-66° C.

260 g of 2,3,6-trimethyl-p-anisaldehyde are introduced into a mixture of3500 ml of acetone and 1400 ml of water and treated with 730 ml of 10wt.% aqueous sodium hydroxide with stirring at 0°-5° C. in the course ofabout 30 minutes. The mixture is stirred for 3 days at room temperatureand subsequently, after lowering of the pH value to 4-5 by addition ofacetic acid, concentrated under reduced pressure. The concentrate isextracted with a total of 3000 ml of diethyl ether. The ether extract iswashed first with 700 ml of an aqueous 5% by weight sodium bicarbonatesolution, then washed with 700 ml of water, dried over sodium sulphateand evaporated under reduced pressure. The remaining oily4-(4-methoxy-2,3,6-trimethyl-phenyl)-but-3-en-2-one boils, afterrectification, at 120°-127° C./0.05 mm Hg.

36.45 g of magnesium are superficially corroded with a small amount ofiodine, introduced into 1000 ml of tetrahydrofuran and treated dropwisewith 162.5 g of ethyl bromide under nitrogen within 45 minutes. In sodoing, the temperature should amount initially to 8°-10° C. It can riseto 25° C. towards the end of the introduction. The reaction mixture isstirred, optionally with renewed addition of a further 5-10 ml of alkylbromide, until the magnesium has gone completely into solution. Theobtained Grignard solution is subsequently added dropwise at 0° C. intoa saturated acetylene/tetrahydrofuran solution manufactured from 650 mlof tetrahydrofuran by gassing for 3 hours with acetylene at -10° to -5°C. The reagent is stirred for 1 hour at 0° C., then treated dropwisewithin 30-45 minutes with acetylene gassing at 0° C., with a solution of218 g of 4-(4-methoxy-2,3,6-trimethyl-phenyl)-but-3 -en-2-one in 250 mlof tetrahydrofuran. The reaction mixture is stirred for 24 hours at 0°C. and subsequently for 12 hours at room temperature, then introducedinto 4.5 kg of ice/water 3.5:1 parts by volume, adjusted to a pH ofabout 4 by the addition of 700 ml of 3 N hydrochloric acid andthoroughly extracted with a total of 3 l of diethyl ether. The etherextract is washed to neutrality with a total of 2 l of water, dried oversodium sulphate and filtered over 20 g of decoloring carbon. Thefiltrate is evaporated under reduced pressure, the remaining5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-penta-4-en-1-yne,after rectification at 125°-135° C./0.04 mm Hg, melts at 58°-60° C.

244 g of5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-3-hydroxy-penta-4-en-1-yneare dissolved in 400 ml of hexane and, after the addition of 45 g of apartially poisoned palladium catalyst, hydrogenated at room temperatureunder normal pressure. The hydrogenation is stopped after about 40-60minutes after the uptake of the amount of hydrogen necessary for thesaturation of the acetyleneethylene bond [25 l]. The hydrogenationsolution is filtered. The filtrate is washed with 300 ml of ethylacetate and evaporated under reduced pressure. The remaining5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-3-hydroxy-pent-1,4-dienemelts at 46°-47° C.

246 g of5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-3-hydroxy-penta-1,4-dieneare dissolved in 2400 ml of benzene. The solution is treated with 343 gof triphenylphosphonium hydrobromide, stirred for 24 hours at 60° C.,then cooled and the benzene separated. The sediment is digested 4 timeswith 500 ml of benzene each time and, after separation of the benzenewashings, dissolved in 700 ml of methylene chloride. The solution isevaporated under reduced pressure. The remaining5-(-4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1-triphenylphosphoniumbromide is dried in vacuo before further processing.

EXAMPLE 4

1775 g of lead tetraacetate (90%) are gradually introduced within 30minutes at 25°-30° C. into a solution of 1000 g of L(+)-tartaric aciddibutyl ester in 3850 ml of benzene. The reaction mixture issubsequently stirred for 1 hour at room temperature. The sediment isfiltered off and extracted with 500 ml of benzene. The benzene extractis evaporated under reduced pressure. The remaining glyoxalic acid butylester boils, after rectification, at 50°-65° C./12 mm Hg.

836 g of the obtained glyoxalic acid butyl ester are introduced into 376g of propionaldehyde. The mixture is treated dropwise at 60° C. with40.8 g of di-n-butylamine. In so doing, the reaction temperature shouldnot rise higher than 106° C. The reaction mixture is then stirred for 2hours at 116°-111° C., cooled and taken up in ether. The diethyl etherextract is washed successively with 500 ml of 1 N sulphuric acid, 700 mlof water, 1000 ml of 5% by weight aqueous sodium bicarbonate solutionand subsequently with 1000 ml of water, dried over sodium sulphate andevaporated under reduced pressure. The remaining 3-formyl-crotonic acidbutyl ester boils, after rectification, at 93°-105° C./14 mm Hg; n²⁵_(D) =1

EXAMPLE 5

28.5 g of5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1-triphenylphosphoniumbromide are introduced under nitrogen gassing into 240 ml of isopropylalcohol. After the addition of 0.12 g of butylated hydroxy toluene, themixture is cooled to -35° C. and treated at this temperature understrong stirring within 5 minutes with 7.50 g of 3-formylcrotyl acetate.The reaction mixture is subsequently mixed with 7.2 g of a 50 wt.%aqueous potassium hydroxide solution--in so doing the temperature shouldnot rise above -25° C.--and, after stirring for 1 hour at -30° C.,introduced into a mixture of 110 g of water, 90 g of ice and 90 ml ofhexane. The hexane layer is separated. The aqueous phase is shaken out 5times with 90 ml of hexane each time. The combined hexane extracts areshaken out 5 times with 180 ml of methanol/water 80:20 parts by volumeeach time. The hexane phase is washed with water, dried over sodiumsulphate and evaporated under reduced pressure. The remaining1-acetoxy-9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraene,an oil, can be purified by absorption on silica gel eluent:hexane/diethyl ether 80:20 parts by volume.

EXAMPLE 6

59 g of 2,3,6-trimethyl-benzyl-triphenylphosphonium bromide and 28 g of7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester are introducedinto 280 ml of abs. ethanol. The mixture is treated dropwise at atemperature between 0° and 10° C. with a solution of 2.72 g of sodium in160 ml of abs. ethanol, subsequently stirred for 48 hours at roomtemperature, then introduced into 800 ml of water and thoroughlyextracted with a total of 3000 ml of hexane. The hexane extract isshaken out 3 times with 1000 ml of methanol/water 60:40 parts by volumeeach time, then dried over sodium sulphate and evaporated under reducedpressure. The remaining9-(2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acidbutyl ester is an oil.

EXAMPLE 7

10 g of9-(2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acidbutyl ester are introduced into 100 ml of abs. ethanol and, after theaddition of a solution of 10 g of potassium hydroxide in 20 ml of water,heated to boiling under nitrogen gassing. The initially cloudy solutionbecoming clear when boiling is cooled after 30 minutes and introducedinto ice-water. The reaction solution is thoroughly extracted, afteracidification with conc. hydrochloric acid, with methylene chloride. Theextract is washed to neutrality with water, dried over calcium chlorideand evaporated under reduced pressure. The remaining9-(2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acidmelts, after recrystallisation from ethyl acetate, at 191°-192° C.

EXAMPLE 8

300 g of pseudocumol are treated dropwise with 700 ml of conc. sulphuricacid. In so doing, the temperature can rise to 40° C. The mixture issubsequently cooled to 20° C. and, after the addition of 450 g ofbromine, stirred for 1 hour at room temperature. Thereafter, 700 ml ofwater are added dropwise. In so doing, the temperature rises to 50° C.The precipitated mixture of solid materials is filtered off anddissolved in 3000 ml of hot water. The insoluble3,5,6-tribromo-1,2,4-trimethylbenzene is separated and rejected. Theaqueous solution is slowly introduced into 1000 ml of 80 wt.% sulphuricacid which is being heated at 180° C. and blown through with steam. The1-bromo-2,3,6-trimethylbenzene coming over with the steam boils at 86°C./6 mm Hg.

250 g of 1-bromo-2,3,6-trimethylbenzene are dissolved in 400 ml ofdiethyl ether. The solution is added dropwise at 20°-30° C. with gentlecooling into a suspension of 66.5 g of magnesium (activated with iodine)and 200 ml of diethyl ether. The mixture is treated dropwise at 20°-30°C. with a solution of 135 g of ethyl bromide in 250 ml of diethyl etherand subsequently heated to boiling under reflux conditions for 3-4hours. As soon as the magnesium has gone into solution, 385 g oforthoformic acid ethyl ester dissolved in 250 ml of abs. diethyl etherare introduced. The reaction mixture is heated to boiling for 5 hours,after evaporation of the diethyl ether poured onto ice, treated with1000 ml of 5 N hydrochloric acid and heated to boiling for 30 minutesunder carbon dioxide gassing. The distillate, obtainable thereafter bywater distillation, is extracted with methylene chloride. The methylenechloride phase is evaporated under reduced pressure. The remaining2,3,6-trimethylbenzaldehyde boils at 70°-72° C./1.2 mm Hg.

129.6 g of 2,3,6-trimethylbenzaldehyde are dissolved in 300 ml ofmethanol and, after the addition of 70 ml of water, cooled to 0°. Themixture is treated portion-wise with 18.25 g of sodium borohydride,stirred for 1 hour, subsequently poured onto ice and thoroughlyextracted with diethyl ether. The ether extract is dried over sodiumsulphate and evaporated under reduced pressure. The remaining2,3,6-trimethylbenzyl alcohol is further processed as follows:

75 g of 2,3,6-trimethylbenzyl alcohol are dissolved in 175 ml oflow-boiling petroleum ether. The solution is treated dropwise within 2hours at -10° C. with a solution of 51 g of phosphorus tribromide in 60ml of low-boiling petroleum ether. The reaction mixture is stirred for12 hours at room temperature, then poured onto ice and extracted withdiethyl ether. The ether extract is washed first with an ice-cold,saturated, aqueous sodium bicarbonate solution, then with a saturatedaqueous common salt solution, dried over sodium sulphate and evaporatedunder reduced pressure. The remaining 2,3,6-trimethylbenzyl bromideboils, after rectification, at 75°-80° C./0.05 mm Hg.

73.3 g of 2,3,6-trimethylbenzyl bromide are dissolved in 170 ml ofbenzene. The solution is treated with 90.0 g of triphenyl phosphine. Inso doing, the temperature rises to 40° C. The mixture is stirred for 12hours at room temperature. The precipitated2,3,6-trimethylbenzyl-triphenylphosphonium bromide melts, after wasingwith low-boiling petroleum ether and drying, at 240°-242° C.

EXAMPLE 9

After the addition of a slight amount of iron (III) nitrate, 2700 ml ofliquid ammonia are treated portion-wise with stirring and cooling with169.5 g of potassium. As soon as the initially blue coloration hasdisappeared, i.e. after about 30-45 minutes, acetylene gas in a streamof 3 l/min, is led in until the dark coloration of the reaction mixturebecomes lighter. Then, the gas stream is reduced to 2 l/min. and themixture treated dropwise with a solution of 500 g ofmethylglyoxal-dimethylacetal in 425 ml of abs. diethyl ether. Thegassing with acetylene is continued for 1 hour with stirring. Thereaction mixture is subsequently treated portion-wise with 425 g ofammonium chloride, gradually warmed to 30° C. within 12 hours withevaporation of the ammonia and extracted with 1600 ml of diethyl ether.The ether extract is dried over sodium sulphate and evaporated underreduced pressure. The remaining 4,4-dimethoxy-3-methylbut-1-yn-3-olboils, after rectification, at 33° C./0.03 mm Hg; n_(D) ²⁵ =1.4480.

198 g of 4,4-dimethoxy-3-methyl-but-1-yn-3-ol are dissolved in 960 ml ofhigh-boiling petroleum ether and, after the addition of 19.3 5%palladium catalyst and 19.3 g of quinoline, hydrogenated under normalconditions. After the uptake of 33.5 l of hydrogen, the hydrogenation isstopped. The catalyst is filtered off. The filtrate is evaporated underreduced pressure. The remaining 4,4-dimethoxy-3-methyl-but-1-en-3-olboils, after rectification, at 70°-72° C./18 mm Hg.

195 ml of phosgene are led into 1570 ml of carbon tetrachloride at -10°C. After the addition of 213 g of pyridine, the solution is treateddropwise at a temperature of -10° to -20° C. with 3274,4-dimethoxy-3-methyl-but-1-en-3-ol. The reaction mixture is slowlywarmed to 25° C. with stirring, stirred for a further 3 hours at roomtemperature, cooled to 15° C. and treated with 895 ml of water. Theaqueous phase is separated and rejected. The organic phase is treated,after standing for 12 hours in the cold, with 448 ml of 5% by weightaqueous sulphuric acid, stirred for 5 hours, then washed with water,dried over sodium sulphate and evaporated under reduced pressure. Theremaining 2-formyl-4-chloro-but-2-ene boils, after rectification, at37°-40° C./1.8 mm Hg; n_(D) ²⁵ =1.4895.

165.7 g of 2-formyl-4-chloro-but-2-ene are dissolved in 840 ml ofbenzene and treated with 367 g of triphenyl phosphine. The reactionmixture is heated to boiling under reflux conditions for 12 hours withnitrogen gassing, then cooled to 20° C. The precipitated2-formyl-but-2-ene-4-triphenyl-phosphonium chloride melts, after washingwith benzene and drying, at 250°-252° C.

212.6 g of 2-formyl-but-2-ene-4-triphenylphosphonium chloride and 95 gof 3-formylcrotonic acid butyl ester are introduced into 1100 ml ofbutanol and treated at 5° C. with a solution of 57 g of triethylamine in60 ml of butanol. The reaction mixture is subsequently stirred for 6hours at 25° C., then cooled and introduced into water and thoroughlyextracted with hexane. The hexane phase is washed first repeatedly withmethanol/water (6:4 parts by volume), then with water, dried over sodiumsulphate and filtered. The filtrate is isomerised for 12 hours byshaking with iodine. The iodine is removed by the addition of sodiumthiosulphate. The filtrate is washed again with water, dried andevaporated under reduced pressure. The remaining7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester boils, afterrectification, at 102°-105° C./0.09 mm Hg.

EXAMPLE 10

By the procedure of Example 6:

2,4,6-triisopropyl-benzyl-triphenylphosphonium bromide is condensed with

7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester to form

9-(2,4,6-triisopropyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid butyl ester (oil);

which is hydrolyzed by the procedure of Example 7 to form:

9-(2,4,6-triisopropyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid m.p.: 221° C.

EXAMPLE 11

136 g of 1,3,5-triisopropyl-benzene, 228 ml of acetic acid, 420 ml ofconc. hydrochloric acid and 55 g of formaldehyde (35%) are heated to 60°C. The reaction mixture is stirred at this temperature firstly for 3hours, then, after the renewed addition of 21 g of formaldehyde (35%),for a further 12 hours, then cooled to room temperature and thoroughlyextracted with benzene. The benzene extract is washed successively withwater, with a saturated aqueous sodium bicarbonate solution and againwith water, dried over sodium sulphate and evaporated under reducedpressure. The remaining 2,4,6-triisopropyl-benzyl chloride boils, afterrectification, at 70° C./0.05 mm Hg.

69.6 g of 2,4,6-triisopropyl-benzyl chloride are dissolved in 1000 ml ofxylene. The solution is treated with 79.5 g of triphenyl phosphine. Themixture is stirred for 18 hours at 125° C., then cooled. The2,4,6-triisopropyl-benzyl-triphenylphosphonium chloride alreadyprecipitated at 80° C. melts, after trituration and washing withbenzene, at 237°-238° C.

EXAMPLE 12

By the procedure of Example 6:

pentamethyl-benzyl-triphenylphosphonium chloride is condensed with

7-formyl-3-methyl-octa-2,4,6-trien-1-oic-acid butyl ester to produce

9-(pentamethyl-phenyl)-3,7-dimethyl-nona,2,4,6,8-tetraen-1-oic acidbutyl ester (oil);

which is hydrolyzed by the procedure of Example 7 to the

9-(pentamethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic-acidm.p.: 228°-229° C.

EXAMPLE 13

184.5 g of pentamethylbenzene, 193 ml of glacial acetic acid, 355 ml ofconc. hydrochloric acid and 44 g of formaldehyde (35%) are heated to 65°C. The reaction mixture is stirred at this temperature first for 3hours, then, after the renewed addition of 18.1 g of formaldehyde (35%)for a further 3 hours, then cooled to room temperature and thoroughlyextracted for a further 12 hours with benzene. The benzene extract iswashed successively with water, diluted aqueous sodium hydroxide andwater, dried over sodium sulphate and evaporated under reduced pressure.The remaining pentamethyl-benzyl chloride melts, after recrystallisationfrom hexane, at 80°-81° C.

101.6 g of pentamethyl-benzyl chloride, 14 g of triphenyl phosphine and250 ml of toluene are stirred for 5 hours at 100° C. Thepentamethyl-benzyl-triphenylphosphonium chloride precipitated withcooling of the reaction mixture, melts, after trituration and washingwith low-boiling petroleum ether, at 258°-259° C.

EXAMPLE 14

16 g of 3-chloro-2,4,6-trimethyl-benzyl-triphenylphosphonium chlorideand 10 g of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl esterare heated to boiling with stirring after the addition of 40 g of1,2-butylene oxide. The 1,2-butylene oxide is slowly distilled off. Thereaction mixture is stirred for 30 minutes at 80°-82° C., then cooledand thoroughly extracted with hexane. The hexane extract is shaken out 5times with 50 ml of methanol/water 70:30 parts by volume each time, thendried over sodium sulphate and evaporated under reduced pressure toproduce 9-(3-chloro-2,4,6-trimethyl-phenyl),3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester as a residue.

EXAMPLE 15

5 g of9-(3-chloro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid butyl ester are heated to boiling under nitrogen gassing in 50 mlof a 5% by weight ethanolic potassium hydroxide solution. The solutionbecoming clear with boiling is cooled after 30 minutes, introduced intowater and made acidic by the addition of the acetic acid. Theprecipitated9-(3-chloro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid melts, after recrystallisation from benzene, at 208°-209° C.

EXAMPLE 16

119 g of chloromesitylene, 11.9 g of paraformaldehyde and 5.95 g of zincchloride (anhydrous) are heated to 60° C. and gassed with hydrogenchloride, with stirring, firstly for 8 hours and, after the addition ofa further 11.9 g of paraformaldehyde, for a further 8 hours. Thereaction mixture is then poured onto ice and thoroughly extracted withdiethyl ether. The ether extract is washed successively with water, witha saturated aqueous sodium bicarbonate solution and with water, driedover sodium sulphate and evaporated. The remaining3-chloro-2,4,6-trimethyl-benzyl chloride boils, after rectification, at138° C./17 mm Hg.

71.25 g of 3-chloro-2,4,6-trimethyl-benzyl chloride, 92 g of triphenylphosphine and 375 ml of abs. toluene are heated at 100° C. for 12 hours.The 3-chloro-2,4,6-trimethyl-benzyl-triphenylphosphonium chlorideprecipitated with cooling melts at 233°-235° C.

EXAMPLE 17

By the procedure given in Example 14

3-nitro-2,4,6-trimethyl-benzyl-triphenylphosphonium chloride iscondensed with

7-formyl-3-methyl-hepta-2,4,6-trien-1-oic acid butyl ester to form

9-(3-nitro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid butyl ester (oil);

which is converted by the procedure of Example 15 to:

9-(3-nitro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid, m.p. 205°-206° C.

EXAMPLE 18

10 g of nitromesitylene, 2 g of p-formaldehyde and 1 g of zinc chloride(anhydrous) are heated to 60° C. and gassed with hydrogen chloride for16 hours with stirring. The reaction mixture is then poured onto ice andthoroughly extracted with diethyl ether. The ether extract is washedsuccessively with water, a saturated, aqueous sodium bicarbonatesolution and with water, dried over sodium sulphate and evaporated. Theremaining 3-nitro-2,4,6-trimethyl-benzyl chloride, an oil, n_(D) ²²=1.5373, is further processed as follows.

11.6 g of 3-nitro-2,4,6-triphenyl-benzyl chloride, 14 g of triphenylphosphine and 100 ml of abs. benzene are heated to boiling under refluxconditions for 24 hours. The3-nitro-2,4,6-trimethyl-benzyl-triphenylphosphonium chlorideprecipitated with cooling melts at 252°-253° C.

EXAMPLE 19

By the procedure of Example 14:

4-methoxy-2,3,5,6-tetramethyl-benzyl-triphenylphosphonium chloride iscondensed with

7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester to form:

9-(4-methoxy-2,3,5,6-tetramethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid butyl ester (oil); which is converted by the procedure of Example15 to:

9-(4-methoxy-2,3,5,6-tetramethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid, m.p. 230°-233° C.

EXAMPLE 20

15 g of 2,3,5,6-tetramethylphenol are dissolved in 55.3 ml of methanoland, after the addition of 7.25 g of potassium hydroxide in 5.5 ml ofwater, treated dropwise at 0°-5° C. with 18.8 g of methyl iodide. Thereaction mixture is stirred for 2 hours at room temperature andsubsequently for 12 hours at 60° C., then cooled, diluted with 150 ml ofwater and extracted with 100 ml of diethyl ether. The ether extract iswashed successively with 3 N sodium hydroxide and water, dried oversodium sulphate and evaporated under reduced pressure. The remaining2,3,5,6-tetramethylanisole melts, after purification by absorption onsilica gel (eluent: methylene chloride), at 53°-55° C.

43 g of 2,3,5,6-tetramethylanisole in 110 ml of acetic acid anhydrousare introduced into 203 ml of 37% by weight aqueous hydrochloric acidand treated dropwise with 21.6 g of 37% formaldehyde. The reactionmixture is heated to 70° C. for 3 hours with stirring and, after therenewed addition of 8.3 g of 37% formaldehyde, stirred for a further 3hours at 70° C. The mixture is subsequently cooled to room temperatureand extracted with 500 ml of benzene. The benzene extract is separated.The aqueous phase is shaken out with benzene. The combined benzeneextracts are washed successively with water, with a saturated, aqueoussodium carbonate solution and again with water, dried and evaporatedunder reduced pressure. The remaining4-methoxy-2,3,5,6-tetramethyl-benzyl chloride melts, afterrecrystallisation from ethyl acetate/hexane (1:3 parts by volume) at104°-105° C.

28 g of 4-methoxy-2,3,5,6-tetramethyl-benzyl chloride, 34.7 g oftriphenyl phosphine and 153 ml of toluene are heated at 100° C. for 12hours. The 4-methoxy-2,3,5,6-tetramethyl-benzyl-triphenylphosphoniumchloride precipitated with cooling melts at 251°-252° C.

EXAMPLE 21

60 g of9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid are dissolved in 1000 ml of acetone. After the addition of 128 g ofmethyl iodide and 128 g of potassium carbonate, the solution is stirredunder nitrogen gassing for 16 hours at 55°-60° C. and subsequentlyevaporated under reduced pressure. The residue is dissolved in 100 ml ofpetroleum ether (boiling point 80°-105° C.). The9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid methyl ester crystallising out at -20° C., melts at 98°-99° C.

EXAMPLE 22

By the procedure of Example 21:

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid and

ethyl iodide is converted to9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester; m.p.: 104°-105° C.;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid and

isopropyl iodide is converted to9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid isopropyl ester; (oil).

EXAMPLE 23

28.6 g of9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid are introduced into 300 ml of benzene and treated under nitrogengassing with 12 g of phosphorus trichloride. The benzene is subsequentlydistilled off under reduced pressure. The remaining9-(4-methoxy-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona,2,4,6,8-tetraen-1-oicacid chloride is dissolved in 1200 ml of diethyl ether. The solution isadded dropwise at -33° C. into 500 ml of liquid ammonia and stirred for3 hours. The reaction mixture is then diluted with 500 ml of diethylether and stirred without cooling for a further 12 hours, the ammoniaevaporating. The residue is dissolved in 10 l of methylene chloride. Thesolution is washed 2 times with 3 l of water, dried over sodium sulphateand evaporated under reduced pressure. The remaining9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid amide melts, after recrystallization from ethanol, at 207°-209° C.

EXAMPLE 24

By the procedure of Example 23:

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid chloride and ethylamine are converted to

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl amide; m.p. 179°-180° C.; and

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid chloride and diethylamine are converted to

9-(4-methoxy-2,3,6,-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid diethyl amide; m.p. 105°-106° C.

EXAMPLE 25

Manufacture of a capsule filling material of the following composition:

    ______________________________________                                        9-(4-Methoxy-2,3,6-trimethyl-                                                 phenyl)-3,7-dimethyl-nona-                                                    2,4,6,8-tetraen-1-oic acid                                                    ethyl ester                0.1 g                                              Wax mixture                51.4 g                                             Vegetable Oil             103.0 g                                             Trisodium salt of ethylenediamine                                             tetraacetic acid           0.5 g                                              Individual weight of a capsule                                                                          150 mg                                              Active material content of a capsule                                                                     10 mg                                              ______________________________________                                    

EXAMPLE 26

Manufacture of an ointment containing 0.3% active material of thefollowing composition:

    ______________________________________                                        9-(4-Methoxy-2,3,6-trimethyl-                                                 phenyl)-3,7-dimethyl-nona-                                                    2,4,6,8-tetraen-1-oic acid                                                                             0.3 g                                                Cetyl alcohol            2.7 g                                                Lanoline                 6.0 g                                                White Vaseline           15.0 g                                               Dist. water q.s. ad      100.0 g                                              ______________________________________                                    

EXAMPLE 27

Manufacture of a water/fat emulsion containing 0.3% active material ofthe following composition:

    ______________________________________                                        9-(4-Methoxy-2,3,6-trimethyl-                                                 phenyl)-3,7-dimethyl-nona-2,4,6,8-                                            tetraen-1-oic acid ethyl amide                                                                          0.3 g                                               Magnsium stearate         2.0 g                                               Perhydrosqualene          13.0 g                                              ______________________________________                                    

EXAMPLE 28

Manufacture of a solution containing 0.1% active material of thefollowing composition:

    ______________________________________                                        9-(4-Methoxy-2,3,6-trimethyl-                                                 phenyl)-3,7-trimethyl-nona-2,4,6,8-                                           tetraen-1-oic acid         0.1 g                                              Dimethyl sulphoxide        70.0 g                                             Water q.s. ad             100 ml                                              ______________________________________                                    

EXAMPLE 29

By the procedure of Example 19-(4-allyloxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester is manufactured from5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1-triphenylphosphoniumbromide by reaction with 3-formyl-crotonic acid ethyl ester. Thisproduct is converted to9-(4-allyloxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid of melting point 198°-200° C. by the procedure of Example 2.

The5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1-triphenylphosphoniumbromide employed as the starting material can be prepared by theprocedure of Example 3. This procedure is carried out by alkylation of1,3,5-trimethylphenol with allyl bromide to give 1,3,5-trimethyl-phenylallyl ether (boiling point 76°-80° C./0.05 mmHg), by formylation of theether obtained to give 4-allyloxy-2,3,6-trimethyl-benzaldehyde (boilingpoint 90°-102° C./0.15 mmHg), by condensation of the aldehyde obtainedwith acetone to give 4-(4-allyloxy-2,3,6-trimethyl-phenyl)-but-3-en-1-al(boiling point 135°-138° C./0.05 mmHg), by reaction of the ketoneobtained with acetylene to give5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-3-hydroxy-penta-4-en-1-yne,by partial hydrogenation of the tertiary acetylene carbinol obtained togive5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-3-hydroxy-penta-1,4-dieneand by reaction of the tertiary ethylene carbinol obtained withtriphenylphosphine hydrobromide. There is obtained5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-triphenylphosphoniumbromide which melts at 114°-116° C.

EXAMPLE 30

By the procedure of Example 14,9-(2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-I-oic acidbutyl ester is manufactured from2,4,6-trimethyl-benzyl-triphenylphosphonium chloride by reaction with7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester. This productis converted to9-(2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acidof melting point 214°-215° C. by the procedure of Example 15.

The 2,4,6-trimethyl-benzyl-triphenylphosphonium chloride employed as thestarting material is prepared by the procedure described in Example 18by haloformylation of mesitylene to give 2,4,6-trimethyl-benzyl chloride(boiling point 112° C./12 mm Hg) and reaction of the latter compoundwith triphenylphosphine.

EXAMPLE 31

By the procedure of Example 14,9-(2,3,4,6-tetramethylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid butyl ester is manufactured from2,3,4,6-tetramethyl-benzyltriphenylphosphonium chloride by reaction with7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester. From thisproduct, there is produced by the procedure of Example 159-(2,3,4,6-tetra-methyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid of melting point 201°-202° C.

The 2,3,4,6-tetramethyl-benzyl-triphenylphosphonium chloride employed asthe starting material is prepared by the procedure described in Example16 by haloformylation of 1,2,3,5-tetramethyl-benzene to give2,3,4,6-tetramethylbenzyl chloride (n_(D) ²⁰ =1.5571) and reaction ofthe latter compound with triphenylphosphine.

EXAMPLE 32

By the procedure described in Example 14,9-(4-methoxy-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid butyl ester is manufactured from4-methoxy-2,6-dimethylbenzyl-triphenylphosphonium chloride by reactionwith 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester. Fromthis product, there is produced by the procedure of Example 15,9-(4-methoxy-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid of melting point 207°-208° C.

The 4-methoxy-2,6-dimethyl-benzyl-triphenylphosphonium chloride employedas the starting material is prepared by the procedure described inExample 16 by haloformylation of 3,5-dimethylanisole to give4-methoxy-2,6-dimethyl-benzyl chloride (n_(D) ²⁰ =1.5475) and reactionof the latter compound with triphenylphosphine.

EXAMPLE 33

By the procedure described in Example 14,9-(3-methoxy-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid butyl ester is manufactured from3-methoxy-2,4,6-trimethyl-benzyl-triphenylphosphonium chloride byreaction with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester.This product is converted to9-(3-methoxy-2,4,6-trimethylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid of melting point 196°-198° C., utilizing the procedure described inExample 15.

The 3-methoxy-2,4,6-trimethyl-benzyl-triphenylphosphonium chlorideemployed as the starting material is prepared by the procedure describedin Example 16 by haloformylation of 2,4,6-trimethylanisole to give3-methoxy-2,4,6-trimethyl-benzyl chloride (n_(D) ²⁷ =1.5415) andreaction of the latter compound with triphenylphosphine. The3-methoxy-2,4,6-trimethyl-benzyltriphenylphosphonium chloride melts at308°-310° C.

EXAMPLE 34

By the procedure described in Example 14,9-(4-methoxy-3-allyl-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid butyl ester is manufactured from4-methoxy-3-allyl-2,6-dimethyl-benzyl-triphenylphosphonium chloride byreaction with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester.This product is converted by the procedure of Example 15 to9-(4-methoxy-3-allyl-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid of melting point 160° C.-161° C.

The 4-methoxy-3-allyl-2,6-dimethyl-benzyl-triphenylphosphonium chlorideemployed as the starting material is prepared by the procedure describedin Example 16 by haloformylation of 3,5-dimethyl-2-allyl-anisole to give4-methoxy-3-allyl-2,6-dimethyl-benzyl chloride (n_(D) ²⁰ =1.5690) andreaction of the latter compound with triphenylphosphine.

EXAMPLE 35

By the procedure described in Example 14,9-(4-methoxy-3-nitro-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester is manufactured from4-methoxy-3-nitro-2,6-dimethyl-benzyl-triphenylphosphonium chloride byreaction with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester.This product is converted by the procedure of Example 15 to9-(4-methoxy-3-nitro-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid of melting point 109°-110° C.

The 4-methoxy-3-nitro-2,6-dimethyl-benzyl-triphenylphosphonium chlorideemployed as the starting material is prepared by the procedure describedin Example 16 by haloformylation of 2-nitro-3,5-dimethyl-anisole to give4-methoxy-3-nitro-2,6-dimethyl-benzyl chloride (melting point 109°-110°C.) and reaction of the latter compound with triphenylphosphine. The4-methoxy-3-nitro-2,6-dimethyl-benzyl-triphenylphosphonium chloridemelts at 230°-232° C.

EXAMPLE 36

By the procedure described in Example 14,9-(4-ethoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester (melting point 96°-97° C.) is manufactured from4-ethoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chloride byreaction with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester.

The 4-ethoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chlorideemployed as the starting material is prepared by the procedure describedin Example 18 by alkylation of 2,3,5-trimethylphenol to give2,3,5-trimethyl-phenyl ethyl ether (melting point 93°-95° C.), byhaloformylation of the ether obtained to give4-ethoxy-2,3,6-trimethyl-benzyl chloride (melting point 63°-64° C.) andby reaction of the latter compound with triphenylphosphine.

EXAMPLE 37

By the procedure described in Example 14,9-(4-isopropoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid butyl ester is manufactured from4-isopropoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chloride byreaction with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester.This product, is converted by the procedure of Example 15 to9-(4-isopropoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid of melting point 176°-177° C.

The 4-isopropoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chlorideemployed as the starting material is prepared by the procedure describedin Example 18 by alkylation of 2,3,5-trimethylphenol to give2,3,5-trimethylphenyl isopropyl ether (boiling point 115° C./11 mmHg),by haloformylation of the ether obtained to give4-isopropoxy-2,3,6-trimethyl-benzyl chloride (n_(D) ²⁰ =1.5433) and byreaction of the latter compound with triphenylphosphine.

EXAMPLE 38

By the procedure described in Example 14,9-(3-dimethylamino-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester (bright-yellow oil) is manufactured from3-dimethylamino-2,4,6-trimethyl-benzyl-triphenylphosphonium chloride byreaction with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester.

The 3-dimethylamino-2,4,6-trimethyl-benzyl-triphenylphosphonium chlorideemployed as the starting material is prepared by the procedure describedin Example 16 by haloformylation of N,N-dimethylmesidine to give3-dimethylamino-2,4,6-trimethyl-benzyl chloride (boiling point 71° C./11mmHg) and reaction of the latter compound with triphenylphosphine.

EXAMPLE 39

1.7 g of 8-diethoxy-phosphono-3,7-dimethyl-octa-2,4,6-trien-1-oic acidethyl ester are introduced in 8.0 ml of tetrahydrofuran. The solution iscooled to 0° C. after addition of 0.27 g of sodiumhydride (50-60%), thenstirred 30 minutes at 0° C. and thereafter a solution of 0.96 g of2,3,6-trimethyl-p-anisaldehyde in 3 ml of tetrahydrofuran is addeddropwise during 15 minutes. The reaction mixture is stirred 7 hours atroom temperature, then poured into ice and, after addition of 2 Nhydrochloric acid, extracted with diethyl ether. The ether extract iswashed neutral with water, dried over sodium sulfate and evaporatedunder reduced pressure. The remaining9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester melts at 104°-105° C.

Instead of sodium hydride (0.27 g), employed above, an alkali metalalcoholate can also be used as condensation agent, e.g. sodium ethylate(0.125 g of sodium in 5 ml ethanol).

EXAMPLE 40

3.03 g of 8-bromo-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl esterare heated with 1.66 g of triethylphosphite slowly to 125° C. Thesurplus bromo ester is distilled off. The residue is cooled and pouredinto ice and extracted with diethyl ether and an aqueous solution ofsodium-hydrogen carbonate, dried and evaporated under reduced pressure.The remaining 8-diethoxy-phosphono-3,7-dimethyl-octa-2,4,6-trien-1-oicacid ethyl ester is immediately treated, as described above, with2,3,6-trimethyl-p-anisaldehyde.

EXAMPLE 41

2 g of 1-(phenyl-sulfonyl)-methyl-4-methoxy-2,3,6-trimethyl-benzene areintroduced in 10 ml of tetrahydrofuran. The solution is cooled to -78°C. and, after the addition of 0.51 g of butyl lithium, treated with asolution of 1.8 g 8-bromo-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethylester in 8 ml of tetrahydrofuran. The reaction mixture is stirred 2hours at -78° C., 2 hours at -40° C. and 16 hours at 0° to +5° C. Themixture is poured into ice and, after addition of 2 N hydrochloric acid,extracted with diethyl ether. The ether extract is washed neutral withwater, dried over sodium sulfate and evaporated under reduced pressure.The remaining9-(4-methoxy-2,3,6-trimethyl-phenyl)-9-(phenyl-sulfonyl)-3,7-dimethyl-nona-2,4,6-trien-1-oicacid ethyl ester (2.8 g) is diluted with 8 ml of abs. ethanol. Thesolution is treated at 0° C. in 2 portions with 1.2 g of sodium ethylatepowder. The mixture is stirred 30 minutes at 0° C., then 2 hours at 80°C., thereafter cooled, poured into ice and, after the addition of 2 Nhydrochloric acid, extracted with diethyl ether. The ether extract iswashed neutral with water, dried over sodium sulfate and evaporatedunder reduced pressure. The remaining9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester melts at 105° to 105° C.

EXAMPLE 42

16.8 g of 4-methoxy-2,3,6-trimethyl-benzyl alcohol, 17.4 g of sodiumsalt of benzene sulfinic acid, 20.0 ml of isopropanol and 30.0 ml ofglacial acetic acid are heated 16 hours under nitrogen and refluxconditions. The reaction mixture is cooled, treated portionwise with 200ml of water and neutralized by the addition of sodium hydrogencarbonate. The organic layer is separated, washed several times with anaqueous solution of sodium hydrogen-carbonate (5% by weight), dried oversodium sulfate and evaporated under reduced pressure. The remaining1-(phenyl-sulfonyl)-methyl-4-methoxy-2,3,6-trimethyl-benzene shows thefollowing I.R.: 1592, 1580, 1302, 1149, 118 cm⁻¹.

EXAMPLE 43

1.08 g of 4-methoxy-2,3,6-trimethyl-benzylchloride, 1.67 g of8-(phenyl-sulfonyl)-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl esterand 10 ml of dimethyl formamide are cooled to 0° C. and treated with0.374 of solid sodium ethanolate. The reaction mixture is stirred 30minutes at room temperature, then poured into ice and, after theaddition of 2 N hydrochloric acid, extracted with diethyl ether. Theether extracted is washed neutral, dried over sodium sulfate andevaporated under reduced pressure. The remaining9-(4-methoxy-2,3,6-trimethyl-phenyl)-8-(phenyl-sulfonyl)-3,7-dimethyl-nona-2,4,6,8-trien-1-oicacid ethyl ester is (as described in Example 42) with the formation ofbenzene sulfonic acid as side product and additional carbon-carbondouble bond in the main product, transformed into the desired9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester (m.p. 104°-105° C.).

EXAMPLE 44

8.5 g of 8-bromo-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl esterare dissolved into 95 ml of dimethyl sulfoxide. The solution is treatedunder nitrogen in the cold with 0.45 g of sodium salt of benzenesulfinic acid. The mixture is stirred 1 hour at room temperature, thenpoured into ice and extracted with diethyl ether. The ether extract iswashed with water, dried over sodium sulfate and evaporated underreduced pressure. The remaining8-(phenyl-sulfonyl)-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl estermelts at 114°-115° C.

EXAMPLE 45

By the procedure of Example 21:

9-(4-methoxy-2,3,5,6-tetramethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester (melting point 105°-106° C.) is manufactured from9-(4-methoxy-2,3,5,6-tetramethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid and ethyl iodide;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid 2-diethylaminoethyl ester (bright-yellow oil) is manufactured from9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid and diethylaminoethyl chloride; and9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid (3-pyridyl)methyl ester (melting point 113°-114° C.) ismanufactured from9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid and beta-picoline chloride.

EXAMPLE 46

20 g of9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid are dissolved in 200 ml of tetrahydrofuran. After the addition of5.5 ml of phosphorus trichloride, the solution is stirred for 2 hours atroom temperature, cooled to 0° C. and treated firstly with 50 ml ofpyridine and then dropwise at 0°-5° C. with 50 ml of propargyl alcohol.The mixture is stirred for 2 hours at room temperature and then dilutedwith water. The organic phase is washed successively with water, dilutehydrochloric acid and a 2% aqueous sodium bicarbonate solution, driedover sodium sulphate and evaporated. There is obtained9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid propargyl ester which melts at 94°-95° C. after absorption onaluminium oxide using benzene as the eluent.

EXAMPLE 47

By the procedure of Example 46:

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid allyl ester (melting point 66°-68° C.) is manufactured from9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid and allyl alcohol.

EXAMPLE 48

By the procedure of Example 23:

9-(4-methoxy-2,3,5,6-tetramethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethylamide (melting point 200°-201° C.) is manufactured from9-(4-methoxy-2,3,5,6-tetramethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid chloride and ethylamine; and9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid morpholide is manufactured from9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid chloride and morpholine.

EXAMPLE 49

15 g of9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester (50:50 cis/trans mixture) are chromatographed on 1.5 kgof aluminium oxide (activity stage 1) using hexane/diethyl ether (80:20parts by volume) as the eluent. From the front, there is isolated9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2-trans,4-cis,6-trans,8-trans-tetraen-1-oicacid ethyl ester as a light-yellow oil.

EXAMPLE 50

The 4-methoxy-2,3,5-trimethyl-benzyl-triphenylphosphonium chlorideemployed as the starting material in Example 51 is prepared in a manneranalogous to that described in the aforegoing Example 8, e.g., by thefollowing sequence:

2,3,6-trimethylphenol

2,3,6-trimethylanisole

4-methoxy-2,3,5-trimethyl-benzyl chloride.

EXAMPLE 51

In analogy to the procedure given in Example 6:

4-methoxy-2,6-dimethyl-3-ethyl-benzyl-triphenyl-phosphonium chloride iscondensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl esterto produce9-(4-methoxy-2,6-dimethyl-3-ethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester which is converted by the procedure of Example 7 toform9-(4-methoxy-2,6-dimethyl-3-ethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid, m.p.: 197°-198° C.

EXAMPLE 52

The 4-methoxy-2,6-dimethyl-3-ethyl-benzyl-triphenylphosphonium chlorideemployed as the starting material in Example 53 can be prepared in amanner analogous to that described in Example 8 by the followingsequence:

3,5-dimethylphenol

1-acetoxy-3,5-dimethyl-benzene

2-acetyl-3,5-dimethyl-phenol

2-ethyl-3,5-dimethyl-phenol

2-ethyl-3,5-dimethyl-anisole

4-methoxy-2,6-dimethyl-3-ethyl-benzyl chloride.

EXAMPLE 53

In analogy to the procedure given in Example 6:

4-methoxy-3,5-diethyl-2,6-dimethyl-benzyl-triphenylphosphonium chlorideis condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethylester to produce the9-(4-methoxy-3,5-diethyl-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester which is converted by the procedure of Example 7 to9-(4-methoxy-3,5-diethyl-2,6-dimethyl-phenyl)acid, m.p: 153°-154° C.

EXAMPLE 54

The 4-methoxy-3,5-diethyl-2,6-dimethyl-benzyl-triphenylphosphoniumchloride employed as starting materials in Example 55 can be prepared ina manner analogous to that described in Example 8 by the followingsequence:

3,5-dimethyl-phenol

1-acetoxy-3,5-dimethyl-benzene

2-acetyl-3,5-dimethyl-phenol

2-ethyl-3,5-dimethyl-phenol

1-acetoxy-2-ethyl-3,5-dimethyl-benzene

6-acetyl-2-ethyl-3,5-dimethyl-phenol

2,6-diethyl-3,5-dimethyl-phenol

2,6-diethyl-3,5-dimethyl-anisole

4-methoxy-3,5-diethyl-2,6-dimethyl-benzyl chloride.

EXAMPLE 55

In analogy to the procedure given in Example 6:

4-propoxy-2,3,6-trimethyl-benzyl-triphenyl-phosphonium chloride iscondensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl esterto produce9-(4-propoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester which is converted by the procedure of Example 7 to9-(4-propoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid, m.p.: 200°-201° C.

EXAMPLE 56

The 4-propoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chlorideemployed as starting material, can be prepared in a manner analogous tothat described in Example 8, e.g., by the following sequence:

2,3,5-trimethylphenol

2,3,5-trimethyl-propoxy-benzene

4-propoxy-2,3,6-trimethyl-benzyl chloride.

EXAMPLE 57

In analogy to the procedure given in Example 6:

4-ethoxy-2,3,6-trimethyl-benzyl-triphenyl-phosphonium chloride iscondensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl esterto produce9-(4-ethoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetranoicacid ethyl ester which is converted by the procedure of Example 7 to9-(4-ethoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid, m.p. 219°-220° C.

EXAMPLE 58

By the procedure of Example 6:

3,5-dichloro-2,4,6-trimethyl-benzyl-triphenyl-phosphonium chloride iscondensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl esterto form9-(3,5-dichloro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester which is converted by the procedure of Example 7 to9-(3,5-dichloro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid, m.p: 220°-222° C.

EXAMPLE 59

In analogy to the procedure given in Example 6:

3-chloro-2,4,6-trimethyl-benzyl-triphenyl-phosphonium chloride iscondensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl esterto produce9-(3-chloro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester, m.p.: 84°-85° C.

EXAMPLE 60

The 3-chloro-2,4,6-trimethyl-benzyl-triphenylphosphonium chlorideemployed as starting material, can be prepared in a manner analogous tothat described in the aforegoing Example 8, e.g., by the followingsequence:

2,4,6-trimethyl-aniline

2,4,6-trimethyl-chlorobenzene

3-chloro-2,4,6-trimethyl-benzyl chloride.

EXAMPLE 61

36.5 g. of1-ethoxycarbonyl-2,6-dimethyl-hepta-1,3,5-trien-7-triphenylphosphoniumbromide are dissolved in 200 ml. of dimethylformamide. The solution is,after addition of 15.0 g. of 4-methoxy-3-butyl-2,6-dimethylbenzylaldehyde, treated at 10° C. dropwise with a solution of 1.64 g. ofsodium in 40 ml. of absolute ethanol. The mixture is subsequentlystirred for 12 hours at room temperature, then introduced into 500 ml.of methanol/water 60:40 parts by volume and thoroughly extracted withhexane. The hexane extract is washed with methanol/water 60:40 parts byvolume, then with water, dried over sodium sulfate and evaporated. Thereis obtained9-(4-methoxy-3-butyl-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester, which is converted, as described in Example 7, into9-(4-methoxy-3-butyl-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid; m.p.: 147°-148° C.

EXAMPLE 62

294 ml. of butyric acid anhydride are treated, after the addition of 2ml. of concentrated aqueous sulfuric acid, at room temperature with 122g. of 3,5-dimethyl-phenol. The temperature rises to 40° C. and is thenraised to 80° C. The mixture is stirred for 1 hour and diluted with 60ml. of water and 60 ml. of ethanol, poured onto ice water and twiceextracted with 500 ml. of hexane each time. The hexane extract is washedwith water, aqueous sodium bicarbonate solution, dried over sodiumsulfate and evaporated. There is obtained 1butyryloxy-3,5-dimethyl-benzene which boils at 123°-125° C./11 mm Hgafter rectification.

180 g. of 1-butyryloxy-3,5-dimethyl-benzene are treated at roomtemperature with 340 g. of aluminium chloride. The mixture is stirredfor 4 hours at 90°-95° C., then cooled at 70° C., poured onto ice and 3n aqueous hydrochloric acid and extracted with ether. The ether extractis washed with water to neutral reaction, dried over sodium sulfate andevaporated. There is obtained 2-butyryl-3,5-dimethyl-phenol, which meltsat 48°-52° C. after recrystalization from petroleum ether.

10 g. of 2-butyryl-3,5-dimethyl-phenol are dissolved in 100 ml. ofglacial acetic acid. After the addition of 3 drops of perchloric acid,the solution is hydrogenated under normal conditions in the presence of0.5 g. of platinum oxide. After the uptake of 3.0 l. of hydrogen, thehydrogenation is stopped. The catalyst is filtered off. The filtrate isextracted with ether. The ether extract is washed with water to neutralreaction, dried over sodium sulfate and evaporated. There is obtained2-butyl-3,5-dimethylphenol, which melts at 65°-67° C. after absorptionon silica gel, using methylene chloride/hexane 1:1 parts by volume asthe eluent.

83 g. of 2-butyl-3,5-dimethyl-phenol are dissolved in 225 ml. ofmethanol. After the addition of 60 g. of potassium hydroxide in 25 ml.of water, the solution is treated at room temperature with 34.2 g. ofmethyl iodide. The mixture is heated to boiling under reflux conditionsfor 3 hours, then cooled, diluted with water and extracted with ether.The ether extract is washed with diluted sodium hydroxide solution,dried over sodium sulfate and evaporated. There is obtained2-butyl-3,5-dimethyl-anisole, which is purified by absorption on silicagel, using hexane/methylene chloride 70:30 parts by volume as theeluent, before processing further.

5.5 ml. of phosphorous oxychloride are added dropwise while stirring to4.6 ml. of dimethylformamide. The temperature rises to 30° C. Themixture is treated dropwise with 9.6 g. of 2-butyl-3,5-dimethyl-anisole,poured onto ice water after the addition of 30 to 35 percent aqueoussolution of sodium acetate, stirred for 1 hour and extracted withbenzene. The benzene extract is washed with water, dried over sodiumsulfate and evaporated. There is obtained4-methoxy-3-butyl-2,6-dimethyl-benzaldehyde, which is purified byabsorption on silica gel, using hexane/methylene chloride 1:1 parts byvolume as the eluent, before the condensation with1-ethoxycarbonyl-2,6-dimethyl-hepta-1,3,5-trien-7-triphenylphosphoniumbromide.

EXAMPLE 63

36 g. of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester aredissolved in 600 ml. of absolute ethanol. The solution is treatedportionwise with 1.8 g. of sodium borohydride. The mixture is stirredfor 2 hours at 10° C., then poured onto ice water and 3 n aqueoushydrochloric acid and extracted with ether. The ether extract is washedsuccessively with water, a saturated aqueous sodium bicarbonate sodiumand once more with water, dried over sodium sulfate and evaporated.There is obtained 8-hydroxy-3,7-dimethyl-octa-2,4,6-trien-1-oic acidethyl ester, which is processed further as follows:

36.5 g. of 8-hydroxy-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethylester are dissolved in 380 ml. of ether. The solution is cooled to 0°C., and after the addition of 3 drops of pyridine treated dropwise with28.6 g. of phosphorous tribromide in 120 ml. of hexane. The mixture isstirred for 20 minutes at 0° C., then poured onto ice water andextracted with ether. The ether extract is washed successively withwater, a saturated aqueous sodium bicarbonate solution and again withwater, dried over sodium sulfate and evaporated. There is obtained8-bromo-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl ester, which isprocessed as follows:

43.7 g. of 8-bromo-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl esterare dissolved in 500 ml. of benzene and treated with 42.0 g. oftriphenylphosphine. The mixture is stirred for 12 hours at roomtemperature, then cooled at 0° C. The precipitated1-ethoxycarbonyl-2,6-dimethyl-hepta-1,3,5-trien-7-triphenylphosphoniumbromide melts at 193°-194° C.

EXAMPLE 64

In analogy to the procedure given in Example 61:

3,4-dimethoxy-2,6-dimethyl-benzaldehyde is condensed with1-ethoxycarbonyl-2,6-dimethyl-hepta-1,3,5-trien-7-triphenylphosphoniumbromide to produce9-(3,4-dimethoxy-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid ethyl ester which is converted by the procedure of Example 7 to9-(3,4-dimethoxy-2,6--dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid, m.p.: 203°-204° C.

EXAMPLE 65

The 3,4-dimethoxy-2,6-dimethyl-benzaldehyde employed as startingmaterial, can be prepared in a manner analogous to that described inExample 64 by the following sequence:

2,4-dimethylphenol

2,4-dimethyl-6-nitro-phenol

2,4-dimethyl-6-nitro-anisole

2,4-dimethyl-6-amino-anisole

2,4-dimethyl-6-hydroxy-anisole

2,4-dimethylveratrole.

EXAMPLE 66

In analogy to the procedure given in Example

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid chloride is reacted with methyl-amine to produce9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid methyl amide, m.p. 206° C.;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid chloride is reacted with isopropyl amine to produce9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid isopropyl amide, m.p. 200° C.;

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid chloride is reacted with butyl amide to produce9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid butyl amide, m.p. 178° C.; and

9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid chloride is reacted with hexylamide to produce9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oicacid hexylamide, m.p. 157°-158° C.

EXAMPLE 679-(4-Methoxy-2,3,6-Trimethylphenyl)-3,7-Dimethyl-2,4,6,8-Nonatetraen-1-ol

In a 5-liter, round bottom flask provided with a stirrer, lowtemperature thermometer, an inlet for dry nitrogen, a gas outlet, and adropping funnel connected to a mineral oil bubbler, were placed 150 g(0.436 moles) of9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester and 800 ml of toluene. The contents were stirred untilthe solids had dissolved, then by means of a dry ice bath, the internaltemperature was lowered to -60° C., at which temperature 780 ml of a 25%solution of diisobutylaluminum (DIBAL) hydride in toluene (1.155 moles)was added dropwise. The initially yellow solution or suspensiongradually deepened in color and after all the DIBAL had been added, thereaction mixture consisted of a clear, somewhat viscous deep red orangesolution. After stirring for one hour, the cooling bath was lowered andthe internal temperature allowed to rise to -40° C., at whichtemperature, 50 ml of a 50% aqueous methanol solution was added dropwisewith intermittent cooling so that when the addition was complete thetemperature was approximately 10° C. At this point, 140 ml of asaturated solution of sodium sulfate was added dropwise. Allowing thetemperature to gradually rise to 25° C. Toward the end of the addition,aluminum hydroxide began to precipitate with the evolution of heat.After stirring for a few minutes, 800 ml of chloroform was added and thesuspension stirred for ten minutes. The precipitate was removed byfiltration on a twelve-inch Buchner funnel through a layer of filteraid, then washed four times with 500 ml portions of chloroform. Thecombined filtrates were washed successively with 600 ml of water, 600 mlof water containing 10 ml of 3 N hydrochloric acid, 600 ml of saturatedsodium bicarbonate solution, and 600 ml of water, then dried overanhydrous sodium sulfate. Distillation of the solvent in the rotaryevaporator left 130-145 g of a crystalline residue. To this was addedone liter of hexane and the suspension stirred vigorously until theaggregates had been dispersed; any material adhering to the walls wasscraped off. The yellow crystalline precipitate was recovered byfiltration, washed twice with sufficient hexane to cover the filtercake, then dried in vacuo first at 12-15 mm (water pump), then at 0.5 mmuntil the weight was constant. The yield of product was 119-123 g, m.p.127.5°-129.5° C.

Distillation of the hexane from the filtrate and washings in the rotaryevaporator left a residue of 12-15 g that crystallized very slowly, andyielded approximately 6-8 g of high quality material.

EXAMPLE 68 Methyl Ether of9-(4-Methoxy-2,3,6-Trimethylphenyl)-3,7-Dimethyl-2,4,6,8-nonatetraene-1-ol

In a 5-l, round bottom flask flushed with nitrogen provided with astirrer, thermometer, gas inlet tube, reflux condenser topped by a gasoutlet connected to a mineral oil bubbler, and a six-inch length ofGooch tubing were placed 156 g (0.5 moles) of9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraene-1-ol,564 g (4 moles) of methyl iodide and 2.5 l of tetrahydrofuran. To thestirred solution, at 20°-25° C., 24 g (1.0 moles) of sodium hydride weregradually added over a period of about one hour from a 500 ml Erlenmeyerflask connected through the Gooch tubing. The yellow solution becameturbid and assumed a brownish tint. Within a few minutes the temperaturerose to 28° C. but was maintained at 25° C. by external cooling. After2.5 hours, the reaction vessel was cooled to 10° C. by an ice bath andthe excess sodium hydride decomposed by the dropwise addition of 50%aqueous methanol. The solvent was then distilled in the rotaryevaporator leaving a partially crystalline residue that was dissolved in500 ml of benzene and transferred to a separatory funnel where it waswashed successively with three 500-ml portions of saturated sodiumbicarbonate solution and once with water containing a little sodiumsulfate. To the benzene solution, 100 mg of butylated hydroxy toluene(BHT) was added, together with anhydrous sodium sulfate, then thesolvent distilled in a rotary evaporator leaving 172 g of an orangesyrup.

This syrup together with another 167 g of a similarly prepared lot wasdissolved in 750 ml of warm hexane and filtered. The stirred solutionwas allowed to crystallize at room temperature for approximately onehour, then the crystallization completed at 0° C., all under nitrogen.The yellow orange crystalline product was recovered by filtration(nitrogen) and washed twice with hexane. After drying, first at 10-15mm, and then at 0.5 mm to constant weight, 266 g (81%) of product wasobtained m.p. 67.5°-69.5° C.

EXAMPLE 69 The n-Butyl Ether of9-(4-Methoxy-2,3,6-Trimethylphenyl)-3,7-Dimethyl-2,4,6,8-Nonatetraen-1-ol

Under nitrogen, 6.0 g of9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nonatetraen-1-ol,(0.0192 moles) was dissolved in 150 ml of tetrahydrofuran containing28.05 g of n-butyliodide in a 250 ml, round bottom, flask provided witha stirrer, thermometer, nitrogen inlet tube, and an opening for theaddition of a solid, through which was added 0.92 g of sodium hydride.The mixture was stirred for 48 hours, then cooled, and the excesshydride decomposed by the cautious addition of methanol. The mixture wasthen diluted with 500 ml of water and extracted with three 50-mlportions of ether. After drying over magnesium sulfate, the solvent wasdistilled in the rotary evaporator and the residue taken up in ten ml ofhexane. On addition of ten ml of methanol, 2.5 g of crystals of thestarting material, m.p. 107°-112° C. were obtained. The filtrate, afterremoval of the solid, was freed of solvent and the residue waschromatographed on 200 g of silica gel. From the fraction eluted with50% ether in hexane was obtained 2.6 g of a solid, which afterrecrystallization from methanol afforded 1.5 g of deep yellow crystals,m.p. 52°-54° C.

We claim:
 1. A compound of the formula: ##STR17## wherein R₁ and R₂ arelower alkyl; R₃ is hydrogen, lower alkyl, lower alkoxy, loweralkenyloxy, nitro, amino, lower alkylamino or alkanoylamino; R₄ is loweralkoxy; R₅ is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, loweralkenyloxy, nitro, amino, lower alkanoylamino or lower alkylamino; andR₆ is formyl, hydroxymethylene or alkoxymethylene; or pharmaceuticallyacceptable salts thereof.